The overall objective of this project is to examine determinants of vaccine protection against primate lentiviruses. Direct evidence supporting the feasibility of vaccine-induced protection against primate lentivirus infection and disease has come from studies in non-human primate models. Using a moderately pathogenic virus, uncloned SIVmne, and its derivative clone E11S, the P.I. previously showed that protection could be achieved by immunization with live recombinant-virus priming followed by subunit antigen boosts. However, the breadth of protection by vaccines based on Env was limited, since only partial protection was achieved against intravenous challenge with uncloned SIVmne. The majority of "breakthrough" viruses recovered from immunized but persistently infected animals had variant sequences in the V1 hypervariable region typical of viruses that evolved during infection of naive animals. Complete protection against the uncloned SIVmne, however, was achieved by the inclusion of both core and envelope antigens in the vaccines. Viruses that have evolved to evade immune responses, to replicate efficiently, and to destroy the host defense system are more likely to overcome vaccine-induced immunity. Based on this assumption, it is hypothesized that the (i) the phenotype of challenge virus, rather than its genotypic relatedness to the vaccine strain per se, is a key determinant of vaccine protection; and (ii) vaccines which induce an array of immune responses against multiple viral targets are more likely to protect against diverse viruses. The P.I. proposes to test these hypotheses by examining the protective efficacy of various multi-component vaccines against viruses of different genetic relatedness and phenotypes. The Specific Aims are: (1) To determine the role of envelope-specific responses in protection against V1-variant viruses that evolved early after infection; (2) To determine the efficacy of Gag/Pol/Env vaccines against sequential homologous isolates; (3) To determine the efficacy of Gag/Pol/Env vaccines against heterologous virus of different virulence; and (4) To examine the role of immunity against viral structural proteins versus accessory gene products in protection. Results from these studies will provide additional insight into factors that affect vaccine protection against primate lentiviruses as well as strategies for the development of broadly effective HIV-1 vaccines.